Several dietary supplements are currently marketed for management of hypertension, but the evidence for effectiveness is conflicting. Our objective was to critically appraise and evaluate the evidence for the effectiveness of chlorogenic acids (CGAs) on blood pressure, using data from published randomized clinical trials (RCTs). Electronic searches were conducted in Medline, Embase, Amed, Cinahl and The Cochrane Library. We also hand-searched the bibliographies of all retrieved articles. Two reviewers independently determined the eligibility of studies and extracted the data. The reporting quality of all included studies was assessed by the use of a quality assessment checklist adapted from the Consolidated Standard of Reporting Trials Statement. Disagreements were resolved through discussion. Seven eligible studies were identified, and five including 364 participants were included. There were variations in the reporting quality of the included RCTs. Meta-analysis revealed a statistically significant reduction in systolic blood pressure in favour of CGA (mean difference (MD): −4.31 mm Hg; 95% confidence interval (CI): −5.60 to −3.01; I2=65%; P<0.00001). Meta-analysis also showed a significant reduction in diastolic blood pressure favouring CGA (MD: −3.68 mm Hg; 95% CI: −3.91 to −3.45; I2=97%; P<0.00001). All studies reported no adverse events. In conclusion, the evidence from published RCTs suggests that CGA intake causes statistically significant reductions in systolic and diastolic blood pressures. The size of the effect is moderate. Few clinical trials have been conducted; they vary in design and methodology and are confined to Asian populations and funded by CGA manufacturers. Large independent trials evaluating the effects of CGA on blood pressure are warranted.
Hypertension is a leading cause of death and a major risk factor for cardiovascular disease.1 Although more than 90% of hypertensive cases are idiopathic,2 dietary and lifestyle factors are major risk factors associated with its increasing incidence.3, 4 Several dietary supplements are currently marketed for the management of hypertension, but the evidence for effectiveness is conflicting.5 One such supplement thought to have an antihypertensive effect is chlorogenic acid (CGA).
CGAs are naturally occurring compounds, which are found in green coffee extracts, that is, unroasted coffee beans.6 The traditional method of extracting green coffee from green coffee bean involves the use of alcohol as a solvent.7 Green coffee extracts are rich in CGA, and this group of polyphenols are believed to be responsible for the biological actions of green coffee. There are four main classes of CGA in green coffee namely: 3-, 4- and 5-caffeoylquinic acids (3-, 4- and 5-CQA), 3,4-, 3,5- and 4,5-dicaffeoylquinic acids (3,4-, 3,5- and 4,5-diCQA), 3-, 4-, and 5-feruloylquinic acids (3-, 4- and 5-FQA), and 3-, 4- and 5-p-coumaroylqunic acids (3-, 4- and 5-p-CoQA).8
CGAs have been postulated to decrease glucose absorption in the intestines through inhibition of glucose 6 phosphatase and decreasing the sodium gradient of apical cells.9 In vitro and animal studies have shown that CGA modulates the activities of hepatic and pancreatic lipases,10, 11 actions which could lead to an inhibition of fat accumulation and stimulation of lipid metabolism.12, 13 Thus extracted CGA-enriched green coffee extract is marketed as a weight loss supplement under a variety of brand names such as ‘Coffee Slender’ and ‘Svetol’.
CGAs are also thought to possess properties beneficial for blood pressure control. They have been hypothesized to have antioxidant activity, demonstrated by their ability to scavenge free radicals in vitro, and increase the antioxidant capacity of plasma in vivo.14, 15 Animal studies have demonstrated that CGAs improve endothelial function and reduce blood pressure by enhancing acetylcholine-induced endothelium-dependent vasodilation,16, 17 and randomized studies in healthy human volunteers have shown that CGA could modulate blood pressure possibly by promoting the effects of nitric oxide and by reducing blood homocysteine levels.18, 19
Clinical trials examining the effects of CGAs on blood pressure have been conducted, and a recent traditional review concluded that dietary intake of CGA could be beneficial for blood pressure management.20 Our objective in this review was to critically appraise and evaluate the evidence for the effectiveness of CGA on blood pressure, using data from published randomized clinical trials (RCTs).
Materials and Methods
We conducted electronic searches in five major English databases: Medline, Embase, Amed, Cinahl and The Cochrane Library. Each database was searched from inception to October 2013. The MeSH terms used included hypertension, hypertens*, antihypertens*, antihypertens*, blood pressure, green coffee, green coffee extract, CGA, caffeic acid, ferulic acid, and derivatives of these (a Medline search strategy has been included as a web supplement; Supplementary Appendix 1). We also searched Google Scholar for relevant conference proceedings using the search terms ‘chlorogenic acid’ and ‘conference’, and hand-searched the bibliographies of all retrieved articles. No age, gender or language restrictions were imposed.
Only double-blinded RCTs were included in this review. To be considered for inclusion, RCTs had to test the effectiveness of orally administered CGA supplement against placebos or identical controls for blood pressure reduction in participants with or without hypertension. Studies had to report blood pressure as outcome measures, and must have had at least four weeks of intervention because the study findings may have implications for public health.21 Studies were included irrespective of lifestyle modification incorporated into the trial. Studies in which CGA was combined with other supplements for blood pressure management were excluded from the review.
Two reviewers (IJO and EAS) independently determined the eligibility of studies. Data extracted by two reviewers (IJO and EAS) included patient characteristics, interventions and results. The reporting quality of all included studies was assessed by the use of a quality assessment checklist (Supplementary Appendix 2) of the Consolidated Standard of Reporting Trials Statement.22 Disagreements were resolved through discussion.
The data were presented as means with standard deviations. Mean changes in systolic and diastolic blood pressures were used as primary endpoints to assess the differences between the CGA and placebo or control groups. Using standard meta-analysis software (RevMan 5.0),23 we generated a risk of bias graph, and computed mean differences (MDs) and 95% confidence intervals (CIs) for studies with sufficient data for statistical pooling. The random-effects model was used for meta-analyses.24 Sensitivity analyses (analysing trials based on study design) were used to test the robustness of overall analyses using the I2 statistic; values of 25, 50 and 75% indicated low, medium and high statistical heterogeneity, respectively. Dose-effect correlations were used to examine the relationship between the dosage of CGA and changes in blood pressure.
Our searches identified 83 non-duplicate citations from which seven eligible studies were identified (Figure 1). Two trials were excluded because their duration was less than 4 weeks.19, 25 Five trials18, 26, 27, 28, 29 including a total of 364 participants were included in the review.
Four trials were of parallel design, whereas one27 was crossover. There were variations in the reporting quality of the included RCTs (Figure 2). No RCT adequately reported randomization and allocation techniques, but three RCTs (60%) reported adequate blinding of study investigators and participants. No RCT clearly reported how outcome assessments were blinded. There was no evidence of selective outcome reporting across the RCTs, but only two RCTs (40%) showed low risk of other biases. All RCTs were conducted in two Asian countries (four in Japan, and one in India; Table 1). Participants in three RCTs26, 28, 29 had mild hypertension, whereas those in two18, 27 were reported to have normal blood pressure; one of which18 included participants with reduced vasodilatory responses. The age of participants in these studies ranged between 22 and 65 years, and the study duration ranged from 4 to 26 weeks, with daily dosages of CGA varying from 25 to 1050 mg (Table 1).
Meta-analysis of the five RCTs (n=507; Figure 3) showed a statistically significant reduction in systolic blood pressure in the CGA group compared with placebo or controls (MD: −4.31 mm Hg; 95% CI: −5.60 to −3.01; I2=65%; P<0.00001). A dose-effect plot showed a significant correlation between CGA dose and reduction in systolic blood pressure (P=0.005; Figure 4). Meta-analysis of three RCTs (n=415) with good evidence of blinding of participants and personnel showed a significant reduction in systolic blood pressure in favour of CGA (MD: −3.20 mm Hg; 95% CI: −4.01 to −2.36; I2=0%; P<0.00001). Meta-analysis excluding the crossover study and participants with normal blood pressure (n=423) also revealed a significant reduction in systolic blood pressure favouring CGA (MD: −3.71 mm Hg; 95% CI: −5.06 to −2.36; I2=63%; P<0.00001). Meta-analysis of the two RCTs with larger sample sizes (n=395) showed a statistically significant reduction in systolic blood pressure favouring CGA over placebo/controls (MD: −3.12; 95% CI: −3.98 to −2.27; I2=0%; P<0.00001).
Meta-analysis of the five RCTs (n=507; Figure 5) showed a significant reduction in diastolic blood pressure favouring CGA over placebo or controls (MD: −3.68 mm Hg; 95% CI: −3.91 to −3.45; I2=97%; P<0.00001). A dose-effect plot excluding two outliers failed to show a significant association between CGA dose and diastolic blood pressure reduction (r=0.6; P=0.1). Meta-analysis of the RCTs excluding participants with normal blood pressure (n=487) revealed a significant reduction in diastolic blood pressure in favour of CGA (MD: −2.45 mm Hg; 95% CI: −2.72 to −2.17; I2=51%; P<0.00001). Meta-analysis of three RCTs with parallel group design and excluding participants with normal blood pressure (n=423) revealed a significant reduction in diastolic blood pressure favouring CGA over placebo or controls (MD: −2.51 mm Hg; 95% CI: −2.79 to −2.23; I2=44%; P<0.00001). Meta-analysis of the RCTs with larger sample sizes (n=395) also showed a significant reduction in diastolic blood pressure in favour of CGA (MD: −2.18 mm Hg; 95% CI: −2.54 to −1.82; I2=0%; P<0.00001).
No adverse events were observed in all the included studies, and the compliance rate was at least 90%. In total, six drop-outs were reported. Three studies26, 28, 29 were wholly funded by manufacturers; one was part-funded by the manufacturer,27 whereas the funding source in one study was not specified.18 Participants in three RCTs18, 26, 29 did not change their lifestyle, whereas those in two RCTs27, 28 had dietary and exercise modifications.
The results of our meta-analyses reveal that supplementation with CGA results in a statistically significant reduction in systolic blood pressure. Our results also show that CGA administration causes small, statistically significant reductions in diastolic blood pressure. The sizes of the effects appear moderate, and the clinical relevance is modest at best. The results of the meta-analysis should be interpreted with caution because of the moderate-to-large statistical heterogeneity observed in the overall analyses and the variation in the study designs and reporting quality of the included studies. To our knowledge, this is the first systematic review evaluating the effects of CGA on blood pressure.
CGAs are involved in the suppression of macrophage infiltration, and thus may be involved in blood vessel remodelling.30 A short-term RCT in humans demonstrated that acute ingestion of CGA-enriched coffee resulted in significant reductions in both systolic and diastolic blood pressures.25 There was evidence of greater flow-mediated dilation and increase in plasma nitric oxide concentration in the CGA group compared with controls, but these did not reach statistical significance. Although it is unclear if the effects could have reached significant levels with longer-term consumption, our results corroborate the study findings on the effects of CGA on blood pressure.
The reduction in systolic blood pressure of 4.1 mm Hg translates to a 3.1% reduction from the baseline across studies, and the decrease in diastolic blood pressure of 3.93 mm Hg equates to 4.6% reduction in these participants; 60% of whom had mild hypertension. Although such reductions appear moderate, they could prove a potentially useful tool in prevention of hypertension if sustained over a longer period. However, due to the variation in the methods applied to the different studies, the trueness of the observed effect is debatable.
A majority of the studies had small sample sizes, which may have biased the study results.31 A lack of clear reporting of randomization and allocation concealment methods compromises the internal validity of the included studies, and consequently limits the firmness of the conclusions that can be drawn on the effects of CGA on blood pressure.32 Similarly, the external validity of the results is also limited as the results may apply only to participants of Asian ethnicity.
The blood pressure reducing properties of CGA constituents—caffeic or ferulic acid—have been studied in animals.33 Intravenous injections of these acids at concentrations of 2.5, 5 and 10 mmol kg−1 revealed that ferulic acid possessed the stronger depressor effect. Human studies have demonstrated that although there is inter-individual variability in the absorption and pharmacokinetics, CGAs have a high bioavailability when consumed orally.8, 34, 35 Though our dose-effect plots suggested some association between daily CGA dosage and blood pressure reduction, there is no established dosage at which CGAs generate reductions in blood pressure.
The extent to which concomitant lifestyle adjustments influenced the results seen in the meta-analyses is uncertain. Apart from coffee, CGA is available in a wide variety of foods including potatoes, fruits and peanuts; on the average, humans are thought to consume approximately 1 g of CGA daily via food intake.16 Whether the extra amount of CGA consumed by trial participants led to an enhancement of its effect on blood pressure is not clear.
The adverse event reports from the included studies suggest that CGA is generally safe. In a previous report, CGA consumption has been reported to increase plasma total homocysteine concentration, which is a risk factor for coronary heart disease.19 Due to the small number of studies conducted in humans, and the short duration of the interventions, we cannot be sure whether consumption of CGA is entirely risk-free and more research is needed.
Strength and limitations
This review has some strength. We used a comprehensive search strategy to identify relevant studies. The results of all the sensitivity analyses undertaken were in the same direction as our overall analysis; analyses of only the large trials resulted in a reduction in the observed heterogeneity, with no change in the direction of the study results. However, we recognize several limitations. We may not have found all RCTs evaluating the effects of CGA on blood pressure, especially unpublished studies. Due to the small number of studies included in the review, we could not use a funnel plot to test for publication bias, and we could not perform subgroup analyses. Furthermore, because all studies took place in Asia, it is unclear whether the effects seen can be replicated in individuals who are not of Asian descent. Finally, the studies identified in our review were largely funded by CGA manufacturers, and this could also have biased the reporting of outcomes.
Well-designed, independently-funded and adequately powered RCTs and including participants of non-Asian descent evaluating the effects of CGA on systolic and diastolic blood pressures are needed. These trials should be of longer-term duration to allow for monitoring of any adverse events associated with the ingestion of CGA. Future investigators should adhere to standardized guidelines when reporting clinical trials results so as to minimize the risk of bias in their studies. To better understand the biologic mechanisms of CGA on blood pressure, well-designed studies with longer duration examining the effects of CGA on flow-mediated dilatation and nitric oxide status in blood vessels are required. Research into the minimum effective dose of CGA, which can generate reductions in blood pressure is also imperative.
The evidence from published RCTs suggests that CGA intake causes statistically significant reductions in systolic and diastolic blood pressures. The size of the effect of CGA is moderate and the clinical relevance is uncertain. Few clinical trials have been conducted; they vary in design and methodology and are all confined to Asian population. Large independent trials evaluating the effects of CGA on blood pressure are warranted.
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The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Journal of Human Hypertension website
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Onakpoya, I., Spencer, E., Thompson, M. et al. The effect of chlorogenic acid on blood pressure: a systematic review and meta-analysis of randomized clinical trials. J Hum Hypertens 29, 77–81 (2015). https://doi.org/10.1038/jhh.2014.46
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